1. Field of Invention
This invention relates to a method and apparatus for producing of radiopharmaceuticals.
2. Description of the Related Art
Cyclotrons are used to generate high energy charged particle beams for purposes such as nuclear physics research and medical treatments. One area where cyclotrons have found particular utility is in the generation of radiopharmaceuticals, also known as biomarkers, for medical diagnosis by such techniques as positron emission tomography (PET). A conventional cyclotron involves a substantial investment, both in monetary and building resources. An example of one of the more compact conventional cyclotrons used for radiopharmaceutical production is the Eclipse RD developed by the company founded by the present inventor and now produced by Siemens. The self-shielded version of the Eclipse RD can be installed in a facility without a shielded vault. The minimum room size for housing the Eclipse RD is 7.31 m×7.01 m×3 m (24 ft×23 ft×10 ft). To support the approximately 29 300 kg (64 400 lbs) installed weight of a self-shielded Eclipse RD, the cyclotron room includes a concrete pad with a minimum thickness of 36 cm (14 in). In addition to a large size and weight, the power requirements often involve a dedicated and substantial electrical power system. The minimum electrical service required for the Eclipse RD is a 208 (±5%) VAC, 150 A, 3-phase service. Thus, medical facilities have a need for biomarkers, but the monetary, structural, and power requirements of conventional cyclotrons have historically made it impracticable for most hospitals and other medical facilities to produce biomarkers on-site.
The half-life of clinically important positron-emitting isotopes, i.e., radionuclides, relative to the time required to process a radiopharmaceutical is a significant factor in biomarker generation. The large linear dimensions of the reaction vessel in radiochemical synthesis systems commonly used in biomarker generators result in a small ratio of surface area-to-volume and effectively limit the heat transfer and mass transport rates and lengthens processing time. The four primary PET radionuclides, fluorine-18, carbon-11, nitrogren-13, and oxygen-15, have short half-lives (approximately 110 min, 20 min, 10 min, and 2 min, respectively).
Consider the case of the production of [18F]2-fluoro-2-deoxy-D-glucose, commonly referred to as [18F]FDG. Converting nucleophilic fluorine-18 ([18F]F−) into [18F]FDG requires up to 45 min using one of the larger conventional radiochemical synthesis systems, such as the Explora FDG4 radiochemistry module, originally developed by a company founded by the present inventor and now produced by Siemens. The processing time is significant with respect to the half-life of the radioisotope. Accordingly, the production yield fraction of a biomarker of a conventional radiopharmaceutical synthesis system is far from ideal, often limited to a range of approximately 50% to 60% of the component substances. For the Explora FDG4, the processing time fraction is approximately 40% of the half-life of the [18F]F− radioisotope. Corrected to the end of bombardment, the Explora FDG4 has an yield fraction of approximately 65%. The limitations of the larger conventional radiochemical synthesis systems are even more evident when preparing biomarkers that are labeled with the radioisotopes having shorter half-lives. A conventional radiopharmaceutical synthesis system is designed to process a significant quantity of radioactivity. For example, the Explora FDG4 accepts up to 333 GBq (9000 mCi) of [18F]F−. During bombardment, a significant percentage of the newly generated radioisotope decays back to its original target state requiring extended bombardment times to produce a sufficient quantity of the radioisotope for use in a conventional radiopharmaceutical synthesis system. For example, the production of approximately 90 GBq (2400 mCi) of [18F]F− requires a bombardment time of approximately 120 min using the Eclipse RD cyclotron. Even with efficient distribution networks, the short half-lives and low yields require production of a significantly greater amount of the biomarker than is actually needed for the intended use. In contrast, the radioactivity of a unit dose of a biomarker administered to a particular class of patient or subject for medical imaging is considerable smaller, generally ranging from 0.185 GBq to 0.555 GBq (5 mCi to 15 mCi) for human children and adults and from 3.7 MBq to 7.4 MBq (100 μCi to 200 μCi) for mice.
Recent advancements have led to the development of smaller reaction systems using microreaction or microfluidic technology. By reducing the linear dimensions of the reaction vessel used in the radiochemical synthesis system, the ratio of surface area-to-volume and, consequently, heat transfer and mass transport rates increases. The smaller size of the reaction vessels lends itself to replication allowing multiple reaction vessels to be placed in parallel to simultaneously process the biomarker. In addition to faster processing times and reduced space requirements, these smaller reaction systems require less energy.
In the radiopharmaceutical area, a 2005 article discusses production of 0.064 GBq (1.74 mCi) of [18F]FDG, a quantity sufficient for several positron emission tomography (PET) imaging studies on mice, using an integrated microfluidic circuit as proof of principle for automated multistep synthesis at the nanogram to microgram scale. Chung-Cheng Lee, et al., Multistep Synthesis of a Radiolabeled Imaging Probe Using Integrated Microfluidics, Science, Vol. 310, no. 5755, (Dec. 16, 2005), pp. 1793, 1796. The authors conclude that their chemical reaction circuit design should eventually yield sufficiently large quantities (i.e., >100 mCi) of [18F]FDG to produce multiple doses for use in PET imaging of humans. The commercially available NanoTek Microfluidic Synthesis System distributed by Advion BioSciences, Inc., can synthesize [18F]FDG 35 times faster than with conventional macrochemistry, which clearly represents a significant improvement in radiopharmaceutical processing time. However, such level of advancement has not been seen with the cyclotrons producing the radioisotopes used in radiopharmaceutical synthesis. However, such level of advancement has not been seen with the cyclotrons producing the radioisotopes used in radiopharmaceutical synthesis.
A conventional cyclotron used in the production of radioisotopes for synthesizing radiopharmaceuticals has significant power requirements. Typically, a conventional cyclotron for radiopharmaceutical production generates a beam of charged particles having an average energy in the range of 11 MeV to 18 MeV, a beam power in the range of 1.40 kW and 2.16 kW, and a beam current of approximately 120 μA. The weight of an electromagnet of such a conventional cyclotron for radiopharmaceutical production typically ranges between 10 tons and 20 tons. The Eclipse RD is an 11 MeV negative-ion cyclotron producing up to two particle beams each with a 40 μA beam current. The major power consuming components of a cyclotron are typically the magnet system power supply, the RF system amplifier, the ion source transformer, the vacuum system cryopump compressor, and the water system. Of these, the magnet system power supply and the RF system amplifier are the most significant. The operating power consumption of the Eclipse RD is specified at 35 kW. The standby power consumption of the Eclipse RD is specified at less than 7 kW. The magnet system of the Eclipse RD produces a mean field of 1.2 T using 3 kW of power. The RF system of the Eclipse RD has a maximum amplifier power of 10 kW. The ion source system of the Eclipse RD is specified for a maximum H− current of 2 mA.
FIG. 1 is a representative illustration of an array of dees in a conventional cyclotron. For simplicity, only two dees 12 are illustrated. However, there are typically four or more dees used. Cyclotrons having fewer dees require more turns in the ion acceleration path, a higher acceleration voltage, or both to energize the ions to the desired level. The dees 12 are positioned in the valley of a large electromagnet and enclosed in a vacuum tank. During operation of the cyclotron, an ion source 81 continuously generates ions 19 through the addition or subtraction of electrons from a source substance. As the ions 19 are introduced into the cyclotron at the center of the array of dees 12, they are exposed a strong magnetic field generated by opposing magnet poles 11 situated above and below the array of dees 12. A radio frequency (RF) oscillator applies a high frequency, high voltage signal to each of the dees 12 causing the charge of the electric potential developed across each of the dees 12 to alternate at a high frequency. Neighboring dees are given opposite charges such that ions 19 entering the gap between neighboring dees 12 see a like charge on the dee behind them and an opposite charge on the dee ahead of them, which results in acceleration (i.e., increasing the energy) of the ions 19. With each energy gain, the orbital radius of the ions 19 increases. The result is a stream of ions 19 following an outwardly spiraling path. The ions 19 ultimately exit the cyclotron as a particle beam 40 directed at a target 89.
FIG. 2 illustrates an exploded view of selected components of a representative conventional two-pole cyclotron using the concept of sector-focusing to constrain the vertical dimension of the accelerated particle beam. The cyclotron includes upper and lower yokes 54 that cooperatively engage when assembled to define an acceleration chamber and opposing upper and lower magnet poles 11. Each magnet pole 11 includes two wedge-shaped pole tips 32, commonly referred to as “hills” where the magnetic flux 58 is mostly concentrated. The recesses between the hills 32 are commonly referred to as “valleys” 34 where the gap between the magnet poles 11 is wider. As a consequence of the wider gap between the magnets poles 11, the magnetic flux density in the valleys 34 is reduced compared to the magnetic flux density in the hills 32. A dee 12 is located in each open space defined by the corresponding upper and lower valleys 34. Vertical focusing of the beam is enhanced by a large hill field-to-valley field. A higher ratio indicates stronger magnetic forces, which tends to confine the beam closer to the median plane of the cyclotron. In principle, a tighter confinement allows reduction of the gap between the magnet poles without increasing the danger of the beam striking the pole faces of the magnet. For a given amount of flux, a magnet with a smaller gap between the magnet poles requires less electrical power for excitation than a magnet with a larger gap between the magnet poles. Once the ions are extracted from the cyclotron and are no longer under the influence of the magnet poles 11, a beam tube 92 directs the particle beam 40 through a collimator 96, which refines the profile of the particle beam 40 for irradiation of the target substance 100 contained in the target 89.
An unfortunate by-product of radioisotope production is the generation of potentially harmful radiation. The radiation generated as a result of operating a cyclotron is attenuated to acceptable levels by a shielding system, several variants of which are well known in the prior art. At the extraction point of a positive ion cyclotron, interaction between the positive ions 19p and the extraction blocks 102 used to induce the positive ions 19p to exit the cyclotron generate prompt high-energy gamma radiation and neutron radiation, a byproduct of nuclear reactions that produce radioisotopes. At the target 89, the nuclear reaction that occurs as the particle beam 40 irradiates the target substance 100 contained therein to produce the desired radioisotope generates prompt high-energy gamma radiation and neutron radiation. Additionally, residual radiation is indirectly generated by the nuclear reaction that yields the radioisotope. During the nuclear reaction, neutrons are ejected from the target substance and when they strike an interior surface of the cyclotron, gamma radiation is generated. Finally, direct bombardment of components such as the collimator 96 and the target window 98 by the particle beam 40 generates induced high-energy gamma radiation. Thus, a cyclotron must be housed in a shielded vault or be self-shielded. Although commonly composed of layers of exotic and costly materials, shielding systems only can attenuate radiation; they cannot absorb all of the gamma radiation or other ionizing radiation.
Following irradiation by the cyclotron, the target substance is commonly transferred to a radioisotope processing system. Such radioisotope processing systems are numerous and varied and are well known in the prior art. The radioisotope processing system prepares the radioisotope for the tagging or labeling of molecules of interest to enhance the efficiency and yield of the radiopharmaceutical synthesis processes. For example, the radioisotope processing system may extract undesirable molecules, such as excess water or metals to concentrate or purify the target substance.